Single-Stage versus Multi-Stage Intramedullary Nailing for Multiple Synchronous Long Bone Impending and Pathologic Fractures in Metastatic Bone Disease and Multiple Myeloma

Simple Summary For patients with advanced metastatic disease presenting with synchronous multiple long bone impending and complete fractures requiring placement of intramedullary nails (IMN), the optimal timing of bone fixation—whether in a single or multiple stages—is still highly debatable. In this work, we compared perioperative outcomes like overall complications, survival, in-hospital death, and postoperative length of stay among others between patients who have undergone single or multi-stage intramedullary nailing procedures for oncological indications. Our findings revealed that single-stage intramedullary nailing synchronous long-bone metastases in select patients does not increase their risk of perioperative complications and in-hospital mortality but leads to earlier postoperative discharge and initiation of rehabilitation. Thus, our results support single-stage multiple nailing as an efficient and viable therapeutic strategy for select patients with multiple long-bone metastases. Abstract Purpose: Determine whether perioperative outcomes differ between patients who have undergone single or multi-stage IMN procedures for impending or completed pathologic fractures. Methods: Patients were classified into single-stage single-bone (SSSB), single-stage multiple-bone (SSMB), and multi-stage multiple-bone (MSMB) based on procedure timing and number of bones involved. Outcome variables compared included length of stay (LOS), in-hospital mortality and survival, initiation of rehabilitation and adjuvant therapy, and perioperative complications. Results: There were 272 IMNs placed in 181 patients (100 males, 81 females, 55.2% and 44.8%, respectively) with a mean age of 66.3 ± 12.1 years. MSMB had significantly longer LOS (24.3 ± 14.2 days) and rehabilitation initiation (3.4 ± 2.5 days) compared to SSSB (8.5 ± 7.7 and 1.8 ± 1.6 days) and SSMB (11.5 ± 7.6 and 2.0 ± 1.6 days) subjects, respectively (both; p < 0.01). Although total perioperative complication rates in SSMB and MSMB were comparable (33.3% vs. 36.0%), they were significantly higher than SSSB (18%) (p = 0.038). MSMB had significantly more (20%) cardiopulmonary complications than SSMB (11.1%) and SSSB (4.5%) (p = 0.027). All groups exhibited comparative survivorship (8.1 ± 8.6, 7.1 ± 7.2, and 11.4 ± 11.8 months) and in-hospital mortality (4.5%, 8.9%, and 4.0%) (all; p > 0.05). Conclusion: In comparison to MSMB, SSMB intramedullary nailing did not result in higher perioperative complication or in-hospital mortality rates in select patients with synchronous long-bone metastases but led to earlier postoperative discharge and initiation of rehabilitation.

Multiple synchronous impending and/or complete pathologic long-bone fractures may be present in patients with advanced metastatic disease. In this unique clinical situation, the prospect of undergoing multiple IMN procedures raises concern of increased perioperative adverse events and mortality [7,8,22]. Early reports of increased theoretical thromboembolic events, severe cardiopulmonary complications, and high mortality rates cautioned against simultaneous IMN of multiple bones under one anesthesia [13,[23][24][25][26][27][28][29] Therefore, IMN insertion in multiple-stages historically emerged as the preferred therapeutic modality, conducting one bone IMN insertion per surgical setting.
Contrary to IMN insertion in multiple stages, nailing of multiple long bones in a single anesthesia offers numerous promising benefits, including a reduction in the number of trips to the operating room, anesthesia burden, and overall healthcare costs, as well as a mitigation of delays in patient rehabilitation, recovery, discharge, and start of definitive adjuvant treatment [28,29]. Despite contradicting the previously reported high complication and mortality rates encountered with single-stage multiple nailing, recent analyses have been limited by their relatively small sample sizes and lack of adequate control groups [10,28,30,31].
Given the absence of a current consensus on the optimal timing of multiple long-bone nailing, this study aims at comparing outcomes of patients with long-bone metastases undergoing multiple IMN insertions under one or multiple surgical settings. With modern anesthesia, minimally invasive surgical techniques, and improvement in perioperative multidisciplinary medical management, we hypothesized that perioperative outcomes will be comparable between all groups.

Patient Population
This study is a retrospective review of a prospectively maintained database, approved by the Institutional Review Board of a single academic urban orthopaedic program. A total of 272 IMNs (181 patients) were inserted between April 2011-December 2020 for metastatic long-bone disease or multiple myeloma ( Figure 1). Seventy (38.7%) patients had at least 2 IMNs inserted, accounting for 161 (59.2%) IMNs.

Group Stratification
Based on the number of bones (one vs. multiple) and timing (one stage vs. multi-stage) of IMN insertion during a single hospital admission, patients were classified into 3 groups: (1) Single-stage multiple-bone (SSMB), undergoing IMN insertion of 2 or more bones in one setting/anesthesia, (2) Multiple-stage multiple-bone (MSMB), undergoing staged IMN insertion of multiple bones, one nail at a time, under different anesthesia on separate days, but same admission, and (3) Single-stage single-bone (SSSB), undergoing only one IMN insertion during a single hospital admission ( Figure 1). These decisions were made with a multidisciplinary team, taking into consideration the patient's tumor burden, general medical condition, rehabilitation potential, timing of adjuvant therapeutic modalities, and patient's and/or their family's wishes.

Preoperative Optimization
Skeletal survey radiographs were obtained for all patients. The decision for prophylactic IMN was predominantly guided by Mirels' criteria [32]. Patients were medically optimized and cleared by a multidisciplinary team including, but not limited to, orthopaedic surgery, anesthesia, internal medicine, hematology-oncology, and rehabilitation. If needed, they were pre-transfused to a hemoglobin level of at least 10 g/dL. When appropriate, lactate-levels were obtained between surgeries to ensure adequate resuscitation (below 2 mmol/L). SSMB had their subsequent procedures performed in the same setting only if they were hemodynamically stable and approved by the anesthesia team. Two planned SSMB had their second procedure aborted during the same setting due to hemodynamic issues, but completed the second nailing procedure at a later date and were therefore included in the MSMB group for analysis. Additionally, one patient had planned staged procedures but died before his second procedure and was classified as SSSB.
Cancers 2023, 15, x FOR PEER REVIEW 3 of 13 Figure 1. The study cohort and patient group overlap. Seven single-stage single-bone (SSSB) subjects had single intramedullary nails (IMNs) placed twice during separate hospitalizations and were counted as 14 unique events, whereas 13 single-stage multiple-bone (SSMB) patients had their surgery preceded or followed by a single-nail insertion during the same hospitalization and were counted in the SSMB cohort for statistical analysis despite them technically undergoing staged procedures. Four SSMB/MSMB (multiple-stage multiple-bone) patients were also considered in the SSSB group as they had a single nail placed in a different hospitalization either before or after the current hospitalization. There was one patient who had undergone a single-and multi-stage multiple-bone nailing procedures during two separate hospitalizations and was included in both SSMB and MSMB groups.

Preoperative Optimization
Skeletal survey radiographs were obtained for all patients. The decision for prophylactic IMN was predominantly guided by Mirels' criteria [32]. Patients were medically optimized and cleared by a multidisciplinary team including, but not limited to, orthopaedic surgery, anesthesia, internal medicine, hematology-oncology, and rehabilitation. If needed, they were pre-transfused to a hemoglobin level of at least 10 g/dL. When appropriate, lactate-levels were obtained between surgeries to ensure adequate resuscitation (below 2 mmol/L). SSMB had their subsequent procedures performed in the same setting only if they were hemodynamically stable and approved by the anesthesia team. Two planned SSMB had their second procedure aborted during the same setting due to hemodynamic issues, but completed the second nailing procedure at a later date and were therefore included in the MSMB group for analysis. Additionally, one patient had planned staged procedures but died before his second procedure and was classified as SSSB.

Primary Demographics
All groups were comparable for age, gender, body mass index (BMI), and primary diagnosis. The most common primary malignancy was multiple myeloma followed by breast and prostate. The most common long bone involved was the femur in all groups, although other differences in procedure location were noted between groups. In contrast Figure 1. The study cohort and patient group overlap. Seven single-stage single-bone (SSSB) subjects had single intramedullary nails (IMNs) placed twice during separate hospitalizations and were counted as 14 unique events, whereas 13 single-stage multiple-bone (SSMB) patients had their surgery preceded or followed by a single-nail insertion during the same hospitalization and were counted in the SSMB cohort for statistical analysis despite them technically undergoing staged procedures. Four SSMB/MSMB (multiple-stage multiple-bone) patients were also considered in the SSSB group as they had a single nail placed in a different hospitalization either before or after the current hospitalization. There was one patient who had undergone a single-and multi-stage multiple-bone nailing procedures during two separate hospitalizations and was included in both SSMB and MSMB groups.

Primary Demographics
All groups were comparable for age, gender, body mass index (BMI), and primary diagnosis. The most common primary malignancy was multiple myeloma followed by breast and prostate. The most common long bone involved was the femur in all groups, although other differences in procedure location were noted between groups. In contrast to SSSB, most procedures in SSMB and MSMB were performed for impending fractures (Table 1).
. † Reported as sample size and percentage: N (%). Each column is assigned a letter alphabetically. The presence of a superscript letter indicates a significant difference between the column in which the superscript letter appears and the column correlated to the superscript letter. The column shaded in gray represents combined values of the SSSB, SSMB, and MSMB groups and was not used for statistical comparison amongst the groups.
The most common combination was femur and humerus in the SSMB and bilateral femur in the MSMB (Table 2). Overlapping patients were placed in more than one group according to their unique clinical course, as well as the timing of their presentation and surgeries, but the data collected were specific for each procedure (or combination of procedures per the defined groups) and admission ( Figure 1). Most femur nails (Gamma 3, Stryker Trauma GmbH, Schönkirchen, Germany or TFNA, Depuy-Synthes GmbH, Oberdorf, Switzerland) were 10 mm. Humeral nails (T2 Proximal Humerus Nail (PHN), Stryker Trauma GmbH, Schönkirchen, Germany) were 8 mm in diameter. Diaphyseal reaming was avoided/minimized and only done when the canal was narrow. No canal venting was performed.

Outcome Variables
Extracted variables from electronic medical records included age, gender, BMI, primary malignancy, surgery details, type (impending or pathologic) and location, number of nails placed, perioperative complications, estimated blood loss (EBL), and packed red blood cell (PRBC) units given intraoperatively or immediately after the procedure in the recovery room. Chart review and discharge summaries were queried to extract postoperative complications, date of return to definitive adjuvant therapy (chemotherapy, radiation), date of initiation of rehabilitation, and date of discharge/ death. Length of stay (LOS) was defined as the number of days between the first surgery and discharge, and mortality was labeled as "in-hospital" when death occurred during the same admission. After discharge, if a definitive date of death was not found after querying all available resources, patients were deemed lost to follow-up. Last follow-up was defined as the date of the last documented visit to the clinic or hospital.

Statistical Analysis
Descriptive analyses were performed to summarize patient demographics, operativevariables, and hospital outcomes. Owing to the variability in EBL and PRBC values, extreme outliers were identified and excluded by subtracting or adding 3 times the interquartile range to the 25th or 75th percentiles, respectively. A one-way analysis of variance with posthoc Tukey was conducted to compare the means of continuous variables among the groups, including patient age, BMI, EBL, PRBC, LOS, return to adjuvant therapy, and initiation of rehabilitation. A Fisher's exact test with Freeman-Halton extension was performed to compare categorical variables between the study cohorts, including gender, fracture type and location, complications, and death. Survivorship was assessed using a log-rank test with Kaplan-Meier estimates. All statistical analyses were conducted in an SPSS version 28.0 (IBM Corporation, Armonk, NY, USA), using a p-value of 0.05 as threshold for statistical significance.

Discussion
Modern advances in cancer diagnosis and treatment have increased survival rates and resulted in a higher incidence and prevalence of metastatic disease [33][34][35]. In patients

Discussion
Modern advances in cancer diagnosis and treatment have increased survival rates and resulted in a higher incidence and prevalence of metastatic disease [33][34][35]. In patients with long-bone metastasis, IMN is regarded as the surgical standard of care for impending and/or complete pathologic fracture fixation [36][37][38][39]. Yet, for subjects presenting with multiple synchronous metastatic long-bone fractures, no consensus currently exists as to whether these procedures should be staged or performed under a single surgical anesthesia.
Contrary to early reports documenting high complication and mortality rates, recent preliminary evidence regarding single-stage nailing of multiple long bones has been encouraging [10,[23][24][25][26][27][28][29][30][31]. However, these limited small series studies lack several clinically relevant variables, and no study has ever compared SSMB vs. MSMB directly. In 16 SSMB (33 IMNs), of whom 12 (75%) underwent combined femur-humerus nailing, Moon et al. noted in-hospital and intraoperative mortality rates of 18.8% and 6.3%, respectively [28]. In another multivariate survivorship analysis of 927 subjects where 35 (3.8%) underwent SSMB surgery (12 bilateral femora and 16 femur-humerus combinations; 34.4% and 45.7%, respectively), SSMB did not show any decreased survival in this group, although only 60% had IMN fixation [22]. The SSMB cohort in our study showed an 8.9% in-hospital death rate with no difference between MSMB and SSSB, possibly highlighting a significant improvement in survival, mortality and complication rates with the implementation of contemporary surgical techniques, medical therapies, and appropriate patient selection over the years.
Data on single-stage bilateral femur nailing in metastatic setting is very limited with a high in-patient mortality rate [10,28,29]. Our limited data on 7 SSMB bilateral femora is encouraging as we found comparable rates of overall complications (1 out of 7, or 14.3% vs. 8 out of 21, or 38.1%; p = 0.37), and inpatient mortality (none vs. 1, or 4.8%) when compared to MSMB bilateral femora (n = 21) during the same admission (Table 4). There were no surgical complications in each group, and cardiopulmonary complications were also comparable (1 out of 7, or 14.3% vs. 5 out 21, or 23.8%, p = 0.52). However, there may be a selection bias and possibility of a type II error, and additional higher-level studies with larger sample size studies are warranted to address the outcomes of single stage bilateral femur nailing.
The SSMB had a shorter LOS as compared to MSMB (11.5 vs. 24.3 days), but comparative to SSSB (8.7 days). Ristevski et al. reported a mean LOS of 26.6 days in bilateral femur cases during the same admission compared to 22.3 days in unilateral cases, but it was not clear whether the procedures in the study were single or multi-staged [10]. Even in traumatic bilateral femur fractures, longer LOS was found in patients undergoing a multi-staged vs. single-stage IMN insertion (28.5 vs. 16.4 days) [40]. Our SSMB were able to initiate postoperative physical therapy earlier (2.03 days) than the MSMB (3.42 days), likely because many MSMB did not start their physical therapy until after their second operation, especially when both lower limbs were involved. Though SSMB were expected to resume definitive adjuvant chemotherapy and/or radiation earlier than the MSMB, we did not find any significant differences between the groups. This may have occurred because many MSMB received adjuvant therapy (specially started radiation to the first operative site) between surgeries. Moreover, several of our patients had their primary medical and oncological care at a different institute and were referred to us only for surgical intervention. Thus, their adjuvant treatment was dependent on several extrinsic factors which impacted the time to resumption of adjuvant therapy.
Our study has several limitations, which may prevent the generalization of our findings. Despite being a retrospective review of a prospectively maintained database, we had a relatively small sample size and some variables were missing. Specifically, definitive death dates, resumption of adjuvant therapy, and initiation of rehabilitation were only available on 40%, 60%, and 80% of patients, respectively. Although MSMB surgery should have the highest cost due to longer LOS as well as multiple trips to the operating room, no actual cost-analysis was performed in this study, as the total cost of cancer treatment depends on multiple factors, of which surgery-related costs are only a small fraction. Due to numerous possible permutations and combinations in the patient population and their presentation with multiple bone involvement in different time frames, some overlap invariably existed between SSSB, SSMB, and MSMB, complicating group stratification, data collection, and statistical analyses. Moreover, in the absence of current guidelines and protocols, the final decision regarding the staging may have contributed to a systematic selection bias, as not all patients were deemed candidates for single-stage fixation. Finally, most study participants were diagnosed with multiple myeloma. This malignancy is prevalent in our community and has a similar surgical treatment compared to other long-bone metastatic diseases; however, its prognosis may be different from the latter. While randomization would have ultimately added more strength to this study, it was not possible due to ethical concerns. Despite such limitations, our findings add value to the growing literature supporting the use of multiple nails in one surgical setting. To the best of our knowledge, ours is the first study of its kind to compare SSSB, SSMB, and MSMB groups with multiple outcome variables.

Conclusions
SSMB IMN insertion in impending/pathological metastatic fracture did not exhibit inferior survivorship, complications, and in-hospital mortality rates compared to MSMB subjects. Most complications were medical (majority cardio-pulmonary) and thus warrant the need for meticulous optimization of these patients before surgery. SSMB IMN insertion also reduced the LOS in hospital and the time to initiation of rehabilitation. Our findings support single-stage multiple nailing as an efficient and viable therapeutic strategy in select patients. Though ours is the first study of its kind with encouraging results, further investigations are warranted to determine an optimal protocol for the surgical management of these complex and medically fragile patients. Informed Consent Statement: Patient consent was waived due to retrospective study design with deidentified patient information.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical considerations.

Conflicts of Interest:
The authors declare no conflict of interest.